The primary goal of this project is to combine linolenic acid (a natural compound from vegetable oils) with an innovative nano-delivery technology to develop a new nanotherapeutic for eradicating Helicobacter pylori (H. pylori) infection burden. This work is driven by our recent discovery that the liposomal formulation of linolenic acid can effectively and rapidly kill both replicating (also called spiral) and dormant (also called coccoid forms of H. pylori bacteria as well as clinically isolated H. pylori strains that are normally resistant to exiting antibiotics. The current standard treatment of H. pylori infection, termed trile therapy, consists of the administration of a proton pump inhibitor (PPI) and two antibiotics (clarithromycin plus amoxicillin or metronidazole). However, the triple therapy is associated with poor compliance of patients, side effects of the antibiotics, and high cost. Moreover, the increasing emergence of H. pylori strains resistant to some of these antibiotics have resulted in a progressive decline in recent years to unacceptable low eradication rates ranging from ~60% to 75%. Herein, we aim to develop a unique and robust nanotherapeutic to treat H. pylori infection with high effectiveness and without adverse side effects. We will test the physicochemical and biological properties and working mechanism of the proposed nanotherapeutics. Using an H. pylori Sydney strain (SS1) mouse model, we will also thoroughly evaluate the antimicrobial efficacy, toxicity and pharmacokinetics of the nanotherapeutics against H. pylori infection. Overall, three specific aims will be addressed in this proposal, including: (i) to investigate the antimicrobial specificity and working mechanism of liposomal linolenic acid (LipoLLA) against H. pylori bacteria; (ii) to engineer a pH-sensitive nanoparticle-stabilized liposome system for smart drug delivery to the stomach mucus lining; and (iii) to test the therapeutic efficacy and toxicity of nanoparticle-stabilized LipoLLA for the treatment of H. pylori infection in a mouse model. The success of this project will provide a new, effective, safe, and inexpensive medication to treat H. pylori infection that will benefit millions of patients. Thi work will also have significant impacts on advancing bioengineering and nanotechnology research by developing a unique and powerful nanoparticle-stabilized liposome system that can tolerate the acidic stomach environment and selectively deliver payloads to the stomach mucus lining. Moreover, this work will also improve the fundamental understanding of how to kill bacteria through disrupting the properties of bacterial plasma membrane and thus avoiding inducing bacterial drug resistance.